Cancer is a heterogeneous group of malignant diseases that, in 2012, were responsible for more than 14% of deaths worldwide. Despite decades of effort, most cancers remain incurable, which is largely due the step change from localized to metastatic disease. Transformed cancer cells are confronted with an innate and adaptive immune surveillance, and it is believed that tumors that developed to become clinically apparent have evolved to evade the immune system (Zitvogel L, et al. Nat Rev Immunol. 2008 8(1):59-73). The notion of increasing the immune system efficacy by therapeutic intervention in order to systemically eradicate cancer cells has long been a vision of oncologists and cancer researchers. A particularly exciting development, hailed by the editors of Science as the scientific breakthrough of 2013 (Couzin-Frankel J. Science. 2013 342(6165):1432-3), is that novel immunotherapeutic strategies show remarkable responses in some patients, especially if combined with common cytotoxic agents. Radiotherapy and chemotherapeutic agents have been shown to substantially enhance tumor-specific immune responses in well-established tumors (Zitvogel L, et al. Nat Rev Immunol. 2008 8(1):59-73; Reits E A, et al. J Exp Med. 2006 203(5):1259-71; Lugade A A, et al. J Immunol. 2005 174(12):7516-23). The synergy between radiation and immunotherapy stems from radiation-induced (i) immunogenic cell death that locally exposes a wealth of tumor antigens, and (ii) release of stress proteins and danger associated molecular patterns (HSPs, DAMPs), which are endogenous immune adjuvants that can stimulate dendritic cell activation (Vatner R E, et al. Front Oncol. 2014 4:325) (FIG. 13C). Most fascinating is the observation that the stimulation of the immune system by localized radiotherapy may modulate systemic regression of metastatic nodules, which is known as the radiation-induced abscopal effect (Demaria S, et al. Int J Radiat Oncol Biol Phys. 2004 58(3):862-70). Such abscopal responses triggered by localized radiotherapy have been reported among others for lymphomas (Antoniades J, et al. Int J Radiat Oncol Biol Phys. 1977 2(1-2):141-7), renal cell carcinomas (Wersall P J, et al. Acta Oncol. 2006 45(4):493-7), papillary adenocarcinomas (Ehlers G, et al. Br J Radiol. 1973 46(543):220-2), but given the large number of patients with metastatic disease these reports remain considered anecdotal (Kaminski J M, et al. Cancer Treat Rev. 2005 31(3):159-72). Abscopal responses can be triggered more reliably through combining irradiation with immunotherapy (Vatner R E, et al. Front Oncol. 2014 4:325). A strong systemic response against squamous cell carcinoma in mice was observed when dendritic cells where administered intratumorally after local irradiation (Akutsu Y, et al. Int J Oncol. 2007 31(3):509-15).
The possibility of rationally inducing abscopal affects using radiotherapy and immunotherapy has the flavor of the long-sought “magic bullet.” But generation of the synergy required to provide local control and to induce the abscopal effect is difficult to predict due to myriad factors including tumor and immune system heterogeneity as well as space and time dependent treatment effects. A wide range of mathematical models has been developed to describe tumor immune interactions at different phases of tumor progression (Kuznetsov V A, et al. Bull Math Biol. 1994 56(2):295-321; Wilkie K P. Adv Exp Med Biol. 2013 734:201-34; d'Onofrio A, et al. Phys Rev E Stat Nonlin Soft Matter Phys. 2011 84(3 Pt 1):031910), or to look at different pathways that are or could be exploited for immunotherapy (Arciero J C, et al. Discret Contin Dyn S. 2004 4(1):39-58; Kirchner D, et al. J Math Biol. 1998 37(3):235-52; Kronik N, et al. PloS one. 2010 5(12):e15482; Kronik N, et al. Cancer Immunol Immunother. 2008 57(3):425-39; Cappuccio A, et al. Cancer Res. 2006 66(14):7293-300), but all focused on a single tumor site. Thus, no prominent inroads have been made to decipher immune-modulated systemic metastatic response triggered by localized radiotherapy.